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Comparative Study of Sildenafil Analogues in the Rabbit Isolated Aorta
Author(s) -
Flores Haroldo A,
Priviero Fernanda BM,
Teixeira Cleber E,
Antunes Edson,
de Nucci Gilberto
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a667-c
Subject(s) - chemistry , soluble guanylyl cyclase , sildenafil , nitric oxide , cgmp specific phosphodiesterase type 5 , biochemistry , pharmacology , medicine , biology , guanylate cyclase , organic chemistry
Aim Sildenafil (SILD), a cGMP‐specific PDE5 inhibitor, relaxes vascular tissues and is used for the treatment of erectile dysfunction. We developed 3 analogue molecules of SILD (SILD‐6, SILD‐7 and SILD‐8). This work aimed to compare the relaxing effects of SILD and SILD‐6, 7 and 8 in the rabbit aorta (RbA). Method Endothelium intact (E+) and denuded (E‐) rings of RbA were mounted in organ baths. Data were recorded in a PowerLab system. Concentration‐response curves (CRC) to SILD, SILD‐6, SILD‐7 and SILD‐8 (1 nM to 10 μM) were obtained in the absence or in the presence of soluble guanylyl cyclase (sGC) activator BAY 42‐2272 (30 nM), nitric oxide synthase or sGC inhibitors, L‐NAME (100 μM) or ODQ (10 μM) respectively. Results In E+ rings, SILD‐6, 7 and 8 induced relaxations in a concentration‐dependent manner, with potency (pEC 50 ) values of 7.27 ± 0.09, 7.32 ± 0.10 and 7.35 ± 0.13, respectively, which were similar to the pEC 50 for SILD (7.29 ± 0.05). Endothelium denudation caused a rightward shift in the CRC for SILD, SILD‐6, 7 and 8 (4, 3, 3.5 and 4.3‐ fold, respectively). Addition of either L‐NAME or ODQ reduced pEC 50 in E+ rings at the same magnitude as the endothelium denudation. However, no additional shift was seen in E‐ rings. Addition of BAY 42‐2272 (30 nM) enhanced the pEC 50 for SILD‐7 (7.74 ± 0.05) in E+ rings and for SILD‐6, 7 and 8 (pEC 50 : 7.34 ± 0.11; 7.10 ± 0.07; 7.13 ± 0.07, respectively) in E‐ rings. SILD‐induced relaxations were not enhanced by BAY in both E+ and E‐ rings. Conclusions Sildenafil and its analogues relax the RbA by a mechanism partially endothelium‐dependent. In E‐ RbA rings, relaxing effects of the SILD analogues are restored by adding the sGC activator BAY 41‐2272. Financial Support: Fapesp